2009 Grants - Furukawa

Structural Insight into Allosteric Inhibition of NMDA Receptors

2009 New Investigator Research Grant

Nerve cells in the brain send rapid signals to one another at specialized structures known as synapses. At many synapses in which a nerve cell excites the next (postsynaptic) cell, the first cell releases the neurotransmitter glutamate (a small chemical messenger). Glutamate rapidly binds to receptors on the postsynaptic cell, causing opening of ion channels that are part of the receptor and subsequent excitation of the postsynaptic cell.

One type of glutamate receptor is known as the N-methyl-D-aspartate (NMDA) receptor. When activated by glutamate, the NMDA receptor allows calcium into the nerve cell. Abnormal calcium influx, caused by dysfunctioning NMDA receptors, has been implicated in cell death associated with Alzheimer's disease. Thus, inhibitors of the NMDA receptor are of interest as potential therapies for the disease.

Hiroyasu Furukawa, Ph.D. and colleagues are studying the structure of the NMDA receptor and the properties of NMDA receptor inhibitors. They are focusing on a type of inhibitor known as allosteric inhibitors, which bind to sites on the receptor different than glutamate. The researchers plan to map the three-dimensional structure of a part of the NMDA receptor that resides on the outside part of the cell membrane and binds allosteric inhibitors.
Dr. Furukawa and colleagues also plan to generate receptors with mutations at specific locations in order to determine the function of each part of the receptor. The goal of this research is to determine how allosteric inhibitors bind to the NMDA receptor, which may help in the subsequent development of inhibitors with the best properties for potential use as drug therapies.